Variant 11-2164240-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000360.4(TH):c.1487T>C(p.Ile496Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,464,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

TH
NM_000360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

Variant links:

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

TH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TH	NM_000360.4 linkuse as main transcript	c.1487T>C	p.Ile496Thr	missense_variant	13/13	ENST00000352909.8	NP_000351.2	P07101-3
TH	NM_199292.3 linkuse as main transcript	c.1580T>C	p.Ile527Thr	missense_variant	14/14		NP_954986.2	P07101-1P78428
TH	NM_199293.3 linkuse as main transcript	c.1568T>C	p.Ile523Thr	missense_variant	14/14		NP_954987.2	P07101-2P78428
TH	XM_011520335.3 linkuse as main transcript	c.1499T>C	p.Ile500Thr	missense_variant	13/13		XP_011518637.1	P07101-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TH	ENST00000352909.8 linkuse as main transcript	c.1487T>C	p.Ile496Thr	missense_variant	13/13	1	NM_000360.4	ENSP00000325951.4	P07101-3
TH	ENST00000381178.5 linkuse as main transcript	c.1580T>C	p.Ile527Thr	missense_variant	14/14	1		ENSP00000370571.1	P07101-1
TH	ENST00000381175.5 linkuse as main transcript	c.1568T>C	p.Ile523Thr	missense_variant	14/14	1		ENSP00000370567.1	P07101-2
TH	ENST00000333684.9 linkuse as main transcript	c.1205T>C	p.Ile402Thr	missense_variant	11/11	1		ENSP00000328814.6	P07101-6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1312650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

641306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000186

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Pathogenic

0.84

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

M;.;.;.

MutationTaster

Benign

0.93

D;D;D;N

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

D;D;.;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;.;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

0.87

P;P;.;P

Vest4

0.31

MutPred

0.45

Loss of stability (P = 1e-04);.;.;.;

MVP

0.99

MPC

1.5

ClinPred

0.97

GERP RS

4.2

Varity_R

0.42

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over